ABSTRACT People with HIV-1 infection smoke at higher rates (40%) than the general population (16%), with non-HIV smokers showing a greater ability to quit. Given the movement of HIV infection from a `fatal' to `chronic' disease, increased smoking rates may negatively impact long-term health outcomes. Understanding why rates are so high remains critical to aiding quit attempts. Given that HIV infection results in inflammation, and nicotine (the primary psychoactive ingredient of tobacco) reduces inflammation, people with HIV may smoke as a means to medicate symptoms. Nicotine exerts numerous effects including improvement in cognitive domains that are deficient in people with HIV. Alternatively, those with HIV may continue to smoke because they experience greater withdrawal effects than the general population. This project will investigate these potential mechanisms. Aim 1 will determine the impact of current smoking on cognitive functioning and use a positron emission tomography (PET) marker to determine neuroinflammation in HIV positive and healthy participants (n=21/gp). Reverse-translated tasks and the NIH Toolkit will characterize the potential positive benefits of smoking satiety in HIV positive participants. Further, current microglia-based neuroinflammatory markers will be determined and compared to cognitive performance. While informative, this cross-sectional analysis will not be able to determine directionality of effects. Hence, Aim 2 will determine directionality of chronic nicotine & withdrawal effects on cognition and neuroinflammation in mice that express the HIV-associated gp120 protein and their wildtype (WT) littermates. In Expt. 1, the effects of chronic nicotine on cognition will be examined using rodent-based tasks from Aim 1. In addition, similar neuroinflammatory markers will be investigated at each stage of treatment (baseline-, acute-, chronic-, and withdrawal-induced effects). In Expt. 2, this work will be repeated in the gp120-mouse model of HIV to determine nicotine's potential interactive effects with this HIV- relevant protein. Finally, Expt. 3 will include antiretroviral treatment (ART; an integrase inhibitor) to determine potential three-way interactions of nicotine, gp120 protein, and ART on cognition and neuroinflammation. Hence, the potential for synergistic enhancement (during nicotine treatment) and deficits (during nicotine withdrawal) on each factor will be determined. Finally, potential changes in dopamine and nicotinic receptor expression will be examined. Hence, these studies will establish the cognitive profile of deficits related to HIV and comorbid cigarette/nicotine use, as well as their link to neuroinflammation. More importantly, using cross- species relevant testing, the `chicken or the egg' conundrum will be answered as to whether those with HIV smoke more and have greater difficulty quitting because of a specific remediation of such deficits with nicotine and/or greater deleterious effects during withdrawal respectively. Neuropathology studies will also help identify potential targets for treatment development and smoking cessation aids to improve the lives of HIV sufferers.